Pilot Project 1

试点项目1：项目总结 肝细胞癌是一种高致命性疾病，其死亡率与发病率呈平行关系。缺乏 晚期肝癌的有效治疗需要深入了解肝癌的分子发病机制和发展 以及评估新的、有针对性的治疗策略。对于肝细胞癌患者，有统计学意义的 非洲裔美国人(AA)/黑人的发病率和死亡率增加，5年存活率下降 患者与非西班牙裔(白人)患者进行比较。在我们对……的理解上有一个知识空白。 AA/黑人和白人患者肝细胞癌种族差异的分子机制分析 TCGA数据库中的RNA序列(RNA-Seq)数据和肝细胞癌肿瘤样本的RNA-Seq数据显示，在 这两组数据显示，在AA/Black患者中，唯一具有统计学意义的激活途径是I型 干扰素(干扰素)信号通路。这一途径由丙型肝炎病毒(丙型肝炎病毒)感染激活，丙型肝炎病毒是一种主要风险 肝细胞癌的发病因素。基于丙型肝炎病毒状态的差异基因表达数据的校正仍被识别为激活 AA/Black肝细胞癌患者中干扰素-I信号转导通路的研究 与丙型肝炎病毒状态无关。肝细胞癌是一种慢性炎症性疾病，干扰素-1作为促肝细胞因子发挥作用。 炎症和免疫抑制细胞因子，建立了研究它们的理论基础。我们假设 干扰素-I信号通路的持续激活可能是AA/Black种族差异的关键决定因素 即使在AA/Black中诱导了干扰素-I诱导基因(ISGs)以响应丙型肝炎病毒感染 患者他们的表达被维持--有助于肝癌的发展和毒力。在这项研究中，角色 在白人和AA/黑人患者中，4-ISG信号在调节肝细胞癌中的作用将使用肝细胞癌进行系统分析 患者来源的异种移植(PDX)细胞株及膳食抗炎化合物的抑制作用 我们将对他们进行评估。拟议的研究将有助于开发一种针对AA/Black的治疗方法 从而对肝癌患者的治疗既有机制上的意义，又有创新性。成功完成 拟议的研究将为数十名AA/黑人肝癌患者的有效治疗创造新的途径 目前还没有有效的治疗选择。

PILOT PROJECT 1: PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. Lack of effective treatment for advanced HCC calls for insights into the molecular pathogenesis of HCC and development and evaluation of novel, targeted therapeutic strategies. For HCC patients, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic (white) patients. There is a gap of knowledge in our understanding of the molecular mechanism underlying the HCC racial disparity between AA/Black and white patients. Analysis of RNA-sequencing (RNA-Seq) data in the TCGA database and RNA-Seq on HCC tumor samples revealed that in both datasets the only pathway that showed statistically significant activation in AA/Black patients is the type I interferon (IFN-I) signaling pathway. This pathway is activated by Hepatitis C virus (HCV) infection, a major risk factor for HCC. Correction of the differential gene expression data based on HCV status still identified activation of IFN-I signaling pathway in AA/Black HCC patients indicating that the observed findings in AA/Black patients are independent of HCV status. HCC is a disease of chronic inflammation and IFN-Is function as pro- inflammatory and immunosuppressive cytokines, establishing the rationale for studying them. We hypothesize that persistent activation of the IFN-I signaling pathway might be a key determinant of racial disparity in AA/Black HCC patients, and even if IFN-I-inducible genes (ISGs) are induced in response to HCV infection in AA/Black patients their expression is maintained—contributing to HCC development and virulence. In this study, the role of a 4-ISG signature in regulating HCC in white and AA/Black patients will be systematically analyzed using HCC patient-derived xenograft (PDX) cell lines and the efficacy of dietary anti-inflammatory compounds in inhibiting them will be evaluated. The proposed studies will help develop a targeted therapeutic approach for AA/Black HCC patients thus having both mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will create new avenues for effective treatment of scores of AA/Black HCC patients for whom currently no effective treatment option is available.